tbuckley/cabot-search huggingface dataset:
Discovery of Targets for Immune–Metabolic Antitumor Drugs Identifies Estrogen-Related Receptor Alpha
Authors: Avinash Sahu, Xiaoman Wang, Phillip Munson, Jan P.G. Klomp, Xiaoqing Wang, Shengqing Stan Gu, Ya Han, Gege Qian, Phillip Nicol, Zexian Zeng, Chenfei Wang, Collin Tokheim, Wubing Zhang, Jingxin Fu, Jin Wang, Nishanth Ulhas Nair, Joost A.P. Rens, Meriem Bourajjaj, Bas Jansen, Inge Leenders, Jaap Lemmers, Mark Musters, Sanne van Zanten, Laura van Zelst, Jenny Worthington, Jun S. Liu, Dejan Juric, Clifford A. Meyer, Arthur Oubrie, X. Shirley Liu, David E. Fisher, Keith T. Flaherty
Journal: Cancer Discovery (2023)

Abstract Drugs that kill tumors through multiple mechanisms have the potential for broad clinical benefits. Here, we first developed an in silico multiomics approach (BipotentR) to find cancer cell–specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway and then used it to identify 38 candidate immune–metabolic regulators. We show the tumor activities of these regulators stratify patients with melanoma by their response to anti–PD-1 using machine learning and deep neural approaches, which improve the predictive power of current biomarkers. The topmost identified regulator, ESRRA, is activated in immunotherapy-resistant tumors. Its inhibition killed tumors by suppressing energy metabolism and activating two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization, and (ii) antigen-presentation stimulation, recruiting CD8+ T cells into tumors. We also demonstrate a wide utility of BipotentR by applying it to angiogenesis and growth suppressor evasion pathways. BipotentR (http://bipotentr.dfci.harvard.edu/) provides a resource for evaluating patient response and discovering drug targets that act simultaneously through multiple mechanisms. Significance: BipotentR presents resources for evaluating patient response and identifying targets for drugs that can kill tumors through multiple mechanisms concurrently. Inhibition of the topmost candidate target killed tumors by suppressing energy metabolism and effects on two immune mechanisms. This article is highlighted in the In This Issue feature, p. 517
Flecainide-Associated QRS Complex Widening—What Really Matters
Authors: Zhenyu Dong, Yanmei Lu, Baopeng Tang
Journal: JAMA Internal Medicine (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Magnetic Resonance Imaging Features of GABA-A Receptor Antibody-Mediated Encephalitis
Authors: Omar Baqal, Aimen Vanood, Ehab Harahsheh
Journal: JAMA Neurology (2023)

This case report describes a patient with status epilepticus and neuroimaging features of fleeting T2 fluid-attenuated inversion recovery hyperintense lesions on magnetic resonance imaging.
Common analgesics and ovarian cancer survival: the Ovarian cancer Prognosis And Lifestyle (OPAL) Study
Authors: Azam Majidi, Renhua Na, Susan J Jordan, Anna DeFazio, Andreas Obermair, Michael Friedlander, Peter Grant, Penelope M Webb
Journal: JNCI Journal of the National Cancer Institute (2023)

Most women with ovarian cancer (OC) are diagnosed with advanced disease. They often experience recurrence after primary treatment, and their subsequent prognosis is poor. Our goal was to evaluate the association between use of nonsteroidal antiinflammatory drugs (NSAIDs), including regular and low-dose aspirin, and 5-year cancer-specific survival after an OC diagnosis.The Ovarian cancer Prognosis And Lifestyle study is a prospective population-based cohort of 958 Australian women with OC. Information was gathered through self-completed questionnaires. We classified NSAID use during the year prediagnosis and postdiagnosis as none or occasional (<1 d/wk), infrequent (1-3 d/wk), and frequent (≥4 d/wk) use. We measured survival from the start of primary treatment: surgery or neoadjuvant chemotherapy for analyses of prediagnosis use, or 12 months after starting treatment (postdiagnosis use) until the earliest of date of death from OC (other deaths were censored) or last follow-up to 5 years. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) and applied inverse-probability of treatment weighting to minimize confounding. We also calculated restricted mean survival times.Compared with nonusers and infrequent users, we observed better survival associated with frequent NSAID use prediagnosis (HR = 0.73, 95% CI = 0.55 to 0.97) or postdiagnosis (HR = 0.65, 95% CI = 0.45 to 0.94). Estimates were similar for aspirin and nonaspirin NSAIDs, new and continuous users and in weighted models. These differences would translate to a 2.5-month increase in mean survival by 5 years postdiagnosis. There was no association with acetaminophen.Our findings confirm a previous study suggesting NSAID use might improve OC survival.
Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis
Authors: Stephanie Meier, Eline A.J. Willemse, Sabine Schaedelin, Johanna Oechtering, Johannes Lorscheider, Lester Melie-Garcia, Alessandro Cagol, Muhamed Barakovic, Riccardo Galbusera, Suvitha Subramaniam, Christian Barro, Ahmed Abdelhak, Simon Thebault, Lutz Achtnichts, Patrice Lalive, Stefanie Müller, Caroline Pot, Anke Salmen, Giulio Disanto, Chiara Zecca, Marcus D’Souza, Annette Orleth, Michael Khalil, Arabella Buchmann, Renaud Du Pasquier, Özgür Yaldizli, Tobias Derfuss, Klaus Berger, Marco Hermesdorf, Heinz Wiendl, Fredrik Piehl, Marco Battaglini, Urs Fischer, Ludwig Kappos, Claudio Gobbi, Cristina Granziera, Claire Bridel, David Leppert, Aleksandra Maleska Maceski, Pascal Benkert, Jens Kuhle
Journal: JAMA Neurology (2023)

There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS).
Microbiome and spatially resolved metabolomics analysis reveal the anticancer role of gut Akkermansia muciniphila by crosstalk with intratumoral microbiota and reprogramming tumoral metabolism in mice
Authors: Zhuxian Zhu, Jixu Cai, Weiwei Hou, Ke Xu, Xuxiao Wu, Yuanlin Song, Chunxue Bai, Yin-Yuan Mo, Ziqiang Zhang
Journal: Gut Microbes (2023)

Although gut microbiota has been linked to cancer, little is known about the crosstalk between gut- and intratumoral-microbiomes. The goal of this study was to determine whether gut Akkermansia muciniphila (Akk) is involved in the regulation of intratumoral microbiome and metabolic contexture, leading to an anticancer effect on lung cancer. We evaluated the effects of gut endogenous or gavaged exogenous Akk on the tumorigenesis using the Lewis lung cancer mouse model. Feces, blood, and tumor tissue samples were collected for 16S rDNA sequencing. We then conducted spatially resolved metabolomics profiling to discover cancer metabolites in situ directly and to characterize the overall Akk-regulated metabolic features, followed by the correlation analysis of intratumoral bacteria with metabolic network. Our results showed that both endogenous and exogenous gavaged Akk significantly inhibited tumorigenesis. Moreover, we detected increased Akk abundance in blood circulation or tumor tissue by 16S rDNA sequencing in the Akk gavaged mice, compared with the control mice. Of great interest, gavaged Akk may migrate into tumor tissue and influence the composition of intratumoral microbiome. Spatially resolved metabolomics analysis revealed that the gut-derived Akk was able to regulate tumor metabolic pathways, from metabolites to enzymes. Finally, our study identified a significant correlation between the gut Akk-regulated intratumoral bacteria and metabolic network. Together, gut-derived Akk may migrate into blood circulation, and subsequently colonize into lung cancer tissue, which contributes to the suppression of tumorigenesis by influencing tumoral symbiotic microbiome and reprogramming tumoral metabolism, although more studies are needed.
Prevaccination Prevalence of Type-Specific Human Papillomavirus Infection by Grade of Cervical Cytology in Estonia
Authors: Anneli Uusküla, Marek Oja, Sirli Tamm, Anna Tisler, Made Laanpere, Lee Padrik, Mari Nygard, Sulev Reisberg, Jaak Vilo, Raivo Kolde
Journal: JAMA Network Open (2023)

Importance Large-scale data on type-specific human papillomavirus (HPV) prevalence and disease burden worldwide are needed to guide cervical cancer prevention efforts. Promoting the research and application of health care big data has become a key factor in modern medical research. Objective To examine the prevaccination prevalence of high-risk HPV (hrHPV) and type distribution by cervical cytology grade in Estonia. Design, Setting, and Participants This cross-sectional study used text mining and the linking of data from electronic health records and health care claims to examine type-specific hrHPV positivity in Estonia from 2012 to 2019. Participants were women aged at least 18 years. Statistical analysis was performed from September 2021 to August 2022. Main Outcomes and Measures Type-specific hrHPV positivity rate by cervical cytological grade. Results A total of 11 017 cases of cervical cytology complemented with data on hrHPV testing results between 2012 and 2019 from 66 451 women aged at least 18 years (mean [SD] age, 48.1 [21.0] years) were included. The most common hrHPV types were HPV16, 18, 31, 33, 51 and 52, which accounted for 73.8% of all hrHPV types detected. There was a marked decline in the positivity rate of hrHPV infection with increasing age, but the proportion did not vary significantly based on HPV type. Implementation of nonavalent prophylactic vaccination was estimated to reduce the number of women with high-grade cytology by 50.5% (95% CI, 47.4%-53.6%) and the number with low-grade cytology by 27.8% (95% CI, 26.3%-29.3%), giving an overall estimated reduction of 33.1% (95% CI, 31.7%-34.5%) in the number of women with precancerous cervical cytology findings. Conclusions and Relevance In this cross-sectional study, text mining and natural language processing techniques allowed the detection of precursors to cervical cancer based on data stored by the nationwide health system. These findings contribute to the literature on type-specific HPV distribution by cervical cytology grade and document that α-9 phylogenetic group HPV types 16, 31, 33, 52 and α-7 phylogenetic group HPV 18 are the most frequently detected in normal-to-high-grade precancerous lesions in Estonia.
HBx-Induced HSPA8 Stimulates HBV Replication and Suppresses Ferroptosis to Support Liver Cancer Progression
Authors: Yufei Wang, Man Zhao, Lina Zhao, Yu Geng, Guanghao Li, Lin Chen, Jingxuan Yu, Hongfeng Yuan, Huihui Zhang, Haolin Yun, Ying Yuan, Guowen Wang, Jinyan Feng, Liang Xu, Shuai Wang, Chunyu Hou, Guang Yang, Ningning Zhang, Wei Lu, Xiaodong Zhang
Journal: Cancer Research (2023)

Abstract Hepatitis B virus (HBV) infection is a major driver of hepatocarcinogenesis. Ferroptosis is a type of iron-mediated cell death that can suppress liver transformation. Previous studies have linked HBV to ferroptosis in liver fibrosis and acute liver failure. However, whether ferroptosis is involved in HBV-mediated liver cancer is poorly understood. Here, we identified heat shock protein family A member 8 (HSPA8) as a crucial host factor that modulates HBV replication and ferroptosis in liver cancer. Hepatitis B X protein (HBx) upregulated HSPA8 by coactivating the transcription factor heat shock factor 1 (HSF1) in cells. HSPA8 enhanced HBV replication by recruiting hepatitis B core protein (HBc) to the HBV covalently closed circular DNA (cccDNA) minichromosome, forming a positive feedback loop. Moreover, HSPA8 suppressed ferroptosis in liver cancer cells by upregulating the expression of SLC7A11/GPX4 and decreasing erastin-mediated reactive oxygen species and Fe2+ accumulation in cells in vitro and in vivo. Inhibition of HSPA8 reduced the growth of HBV-positive liver tumors and increased sensitivity to erastin. In conclusion, HBx-elevated HSPA8 regulates both HBV replication and ferroptosis in liver cancer. Targeting HSPA8 could be a promising strategy for controlling HBV and hepatocarcinogenesis. Significance: HBV-induced upregulation of HSPA8 promotes hepatocarcinogenesis by suppressing ferroptosis and stimulating HBV replication, identifying HSPA8 as a potential therapeutic target in liver cancer.
Injectable hydrogels for sustained delivery of extracellular vesicles in cartilage regeneration
Authors: Sanne M. van de Looij, Olivier G. de Jong, Tina Vermonden, Magdalena J. Lorenowicz
Journal: Journal of Controlled Release (2023)

Extracellular vesicles (EVs) are a population of small vesicles secreted by essentially all cell types, containing a wide variety of biological macromolecules. Due to their intrinsic capabilities for efficient intercellular communication, they are involved in various aspects of cellular functioning. In the past decade, EVs derived from stem cells attracted interest in the field of regenerative medicine. Owing to their regenerative properties, they have great potential for use in tissue repair, in particular for tissues with limited regenerative capabilities such as cartilage. The maintenance of articular cartilage is dependent on a precarious balance of many different components that can be disrupted by the onset of prevalent rheumatic diseases. However, while cartilage is a tissue with strong mechanical properties that can withstand movement and heavy loads for years, it is virtually incapable of repairing itself after damage has occurred. Stem cell-derived EVs (SC-EVs) transport regenerative components such as proteins and nucleic acids from their parental cells to recipient cells, thereby promoting cartilage healing. Many possible pathways through which SC-EVs execute their regenerative function have been reported, but likely there are still numerous other pathways that are still unknown. This review discusses various preclinical studies investigating intra-articular injections of free SC-EVs, which, while often promoting chondrogenesis and cartilage repair in vivo, showed a recurring limitation of the need for multiple administrations to achieve sufficient tissue regeneration. Potentially, this drawback can be overcome by making use of an EV delivery platform that is capable of sustainably releasing EVs over time. With their remarkable versatility and favourable chemical, biological and mechanical properties, hydrogels can facilitate this release profile by encapsulating EVs in their porous structure. Ideally, the optimal delivery platform can be formed in-situ, by means of an injectable hydrogel that can be administered directly into the affected joint. Relevant research fulfilling these criteria is discussed in detail, including the steps that still need to be taken before injectable hydrogels for sustained delivery of EVs can be applied in the context of cartilage regeneration in the clinic.
Bariatric Surgery May Cut Esophageal, Gastric Cancer Risk
Journal: Cancer Discovery (2023)

A large retrospective study of patients who are severely obese in France suggests that bariatric surgery may reduce the risk of gastric and esophageal cancers, alleviating concerns that surgery may increase such risk. Studies with longer follow-up and more histologic data are needed to better understand the connection between surgical procedures and subtypes of these cancers.
Dysregulated Smooth Muscle Cell BMPR2–ARRB2 Axis Causes Pulmonary Hypertension
Authors: Lingli Wang, Jan-Renier Moonen, Aiqin Cao, Sarasa Isobe, Caiyun G. Li, Nancy F. Tojais, Shalina Taylor, David P. Marciano, Pin-I. Chen, Mingxia Gu, Dan Li, Rebecca L. Harper, Nesrine El-Bizri, Yu-Mee Kim, Kryn Stankunas, Marlene Rabinovitch
Journal: Circulation Research (2023)

Mutations in
Slower Calcium Handling Balances Faster Cross-Bridge Cycling in Human <i>MYBPC3</i> HCM
Authors: Josè Manuel Pioner, Giulia Vitale, Sonette Steczina, Marianna Langione, Francesca Margara, Lorenzo Santini, Francesco Giardini, Erica Lazzeri, Nicoletta Piroddi, Beatrice Scellini, Chiara Palandri, Maike Schuldt, Valentina Spinelli, Francesca Girolami, Francesco Mazzarotto, Jolanda van der Velden, Elisabetta Cerbai, Chiara Tesi, Iacopo Olivotto, Alfonso Bueno-Orovio, Leonardo Sacconi, Raffaele Coppini, Cecilia Ferrantini, Michael Regnier, Corrado Poggesi
Journal: Circulation Research (2023)

Background: The pathogenesis of MYBPC3 -associated hypertrophic cardiomyopathy (HCM) is still unresolved. In our HCM patient cohort, a large and well-characterized population carrying the MYBPC3 :c772G&gt;A variant (p.Glu258Lys, E258K) provides the unique opportunity to study the basic mechanisms of MYBPC3 -HCM with a comprehensive translational approach. Methods: We collected clinical and genetic data from 93 HCM patients carrying the MYBPC3 :c772G&gt;A variant. Functional perturbations were investigated using different biophysical techniques in left ventricular samples from 4 patients who underwent myectomy for refractory outflow obstruction, compared with samples from non-failing non-hypertrophic surgical patients and healthy donors. Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and engineered heart tissues (EHTs) were also investigated. Results: Haplotype analysis revealed MYBPC3 :c772G&gt;A as a founder mutation in Tuscany. In ventricular myocardium, the mutation leads to reduced cMyBP-C (cardiac myosin binding protein-C) expression, supporting haploinsufficiency as the main primary disease mechanism. Mechanical studies in single myofibrils and permeabilized muscle strips highlighted faster cross-bridge cycling, and higher energy cost of tension generation. A novel approach based on tissue clearing and advanced optical microscopy supported the idea that the sarcomere energetics dysfunction is intrinsically related with the reduction in cMyBP-C. Studies in single cardiomyocytes (native and hiPSC-derived), intact trabeculae and hiPSC-EHTs revealed prolonged action potentials, slower Ca 2+ transients and preserved twitch duration, suggesting that the slower excitation-contraction coupling counterbalanced the faster sarcomere kinetics. This conclusion was strengthened by in silico simulations. Conclusions: HCM-related MYBPC3 :c772G&gt;A mutation invariably impairs sarcomere energetics and cross-bridge cycling. Compensatory electrophysiological changes (eg, reduced potassium channel expression) appear to preserve twitch contraction parameters, but may expose patients to greater arrhythmic propensity and disease progression. Therapeutic approaches correcting the primary sarcomeric defects may prevent secondary cardiomyocyte remodeling.
Improving rural cancer prevention: targeted data and understanding rural-specific factors and lived experiences
Authors: Sarah Nechuta, Heather Wallace
Journal: JNCI Journal of the National Cancer Institute (2023)

Approximately 46 to 59 million US residents live in counties defined as nonmetropolitan or rural depending on the definition used (1,2).(Note that rural and nonmetropolitan will be used interchangeably in this editorial for brevity unless otherwise specified.)For the first time since 2010, population growth in rural counties increased during 2020-2021 (1).The number of older Americans in rural areas continues to increase with more than 20% of the rural population aged 65 years or older, partly because of in-migration of older adults and out-migration of young adults (1).Although cancer deaths continue to decline in the United States, age-adjusted cancer mortality rates are higher among men and women in rural areas (compared with men and women in urban areas) with a widening trend in rural-urban differences by sex between 1999 and 2019 (3).In 2020, the US age-adjusted cancer mortality rate was 164 per 100 000 in rural populations and 140 per 100 000 in urban populations (4).Research examining rural-urban mortality disparities by cancer type consistently find higher cancer mortality burden among rural populations for preventable cancers (5-7).Unhealthy behaviors and cancer risk factors that play a role in the etiology and survival of major cancers including physical inactivity, obesity, and smoking are more prevalent in rural compared with urban populations (8-13).Many rural Americans are both underserved and socially disadvantaged with more poverty, lower education, lack of health insurance, and lack of broadband access (13-15).Economic and social inequities may be even higher among rural racial and ethnic minorities or differ among racial and ethnic groups in rural populations (8,15,16), highlighting the importance of understanding cancer burden jointly by rurality and race and ethnicity.These differences in health behaviors, demographics, and social factors have important implications for cancer prevention and control in rural communities in the United States.In this issue of the Journal, Oh et al. ( 17) conducted a large population-based study to examine rurality using a novel measure in association with cancer incidence trends during 2015-2019 overall for the top 5 cancer types in California (breast, prostate, melanoma, lung, and colorectal) and by sex and race and ethnicity.They used the proportion of rural residence within census tract aggregation zones to define rurality across 7 levels.The authors addressed 2 key limitations noted in previous rural cancer research by going beyond a dichotomous measure of rurality and not using broad county-level comparisons, which can result
A Versatile Design‐Enabled Analysis of Circulating Extracellular Vesicles in Disease Diagnosis
Authors: Qi Liu, Jianhua Yao, Zichen Huang, Shuning Wang, Jizong Jiang, Ya Cao, Yihua Bei, Jing Zhao
Journal: Advanced Healthcare Materials (2023)

Abstract Circulating extracellular vesicles (EVs) are considered as potential biomarkers for treatment and diagnosis of many diseases. Most of the existing methods for the EV analysis only have a single function and thus reveal limited information carried by EVs. Herein, a phosphatidylserine‐targeting peptide‐facilitated design that enables the versatile analysis of circulating EVs for varying requirement is proposed. In the design, DNA probes are inserted into the EV membrane through hydrophobic interactions, and accelerate the removal of protective shielding from DNA‐gated metal–organic framework, thereby releasing a large number of methylene blue molecules to amplify the electrochemical signal. Electrochemical results demonstrate equally high sensitivities toward the quantification of EVs derived from different cell sources using an indiscriminative DNA probe. More importantly, the probe can be endowed with extended function for more accurate classification of cell‐specific features through the identification of specific EV biomarkers, and demonstrates the potential use in the diagnosis of cardiovascular in a principle‐of‐proof study for clinical application. Therefore, the method provides a versatile design for the identification of EV features, and may address the needs of clinical diagnosis in the future.